Acquired immunodeficiency syndrome (AIDS) is caused by human immunodeficiency virus (HIV) that infects and destroys helper T-lymphocytes. The general objective of this work is to devise strategies for introducing new genes into lymphocytes that will render them resistant to HIV infection. This approach has been described as "intracellular immunization". We first attempted antisense RNA inhibition of HIV replication but this strategy has proven to be ineffective. During the past year we have focused our attention on utilizing the HIV virus to develop a new gene transfer system. This virus gains entry into T-cells by virtue of interaction of its membrane glycoprotein with a cellular protein, CD4. A packaging system has been created that utilizes the genes encoding HIV proteins, contained on a "packaging" plasmid, to direct synthesis of these proteins in monkey kidney cells. Simultaneously, a recombinant plasmid containing the HIV replication, transcription and integration signals but lacking structural genes is introduced into these cells. Recombinant retroviral particles are produced that are targeted specifically to CD4 expressing cells. This system has been shown to be highly efficient and offers a number of significant advantages over murine based retroviral vectors.